2013 Grants - Salehi

Improving ß2 Adrenergic Signaling in Alzheimer's Disease

2013 Part the Cloud Translational Research Bridge Funding for Alzheimer's Disease in Northern California

Nerve cells in the brain send signals to one another by releasing chemicals called neurotransmitters that bind to specific sites on other nerve cells and activate or inhibit a cell's activity. One of the neurotransmitters in the brain is called norepinephrine; it is released by specific types of nerve cells located in a region called the locus coeruleus or "LC". Scientists have observed that nerve cells in the LC are especially vulnerable to damage during Alzheimer's disease.

Specific binding sites for norepinephrine are known as adrenergic receptors. One type of these receptors, known as beta2-adrenergic receptor, are found in parts of the brain that receive signals from the LC, which is important for learning and memory. Decreased beta2-adrenergic signaling, as occurs when norepinephrine cells from the LC are damaged in Alzheimer's disease, may contribute to impairments in learning and memory.

Researchers working at the Palo Alto Institute for Research and Education, Inc., have been studying the role of beta2-adrenergic receptors in Alzheimer's disease. Using animal models of the disease, the researchers have shown that drugs to activate beta2-adrenergic receptors in the brain can improve learning and brain structure in these animals, acting in a way to replace the norepinephrine lost when LC cells become less function or die.

The research team, led by Ahmad Salehi, M.D., Ph.D., has proposed a first-step clinical trial of such a drug in 40 people who have moderate Alzheimer's disease. The drug, known as formoterol, is already in use in humans to treat breathing problems, so its dosing and safety characteristics are already known. Participants in the clinical trial will receive formoterol for six months, along with another drug to block unwanted effects of formoterol in parts of the body other than the brain. The researchers will monitor the effects of formoterol in the brain by measuring brain function, biological markers of Alzheimer's disease and changes in brain structure on brain imaging.

Brain function will be measured using tests of thinking and learning abilities. The biological markers that will be measured are levels of beta-amyloid and tau in the cerebrospinal fluid. Beta-amyloid and tau are the two primary molecules in the hallmarks of the disease, plaques and tangles and are being focused on as causes of Alzheimer's disease. Previous studies have shown that levels of these two molecules in the cerebrospinal fluid, the fluid that surrounds the brain, change during the onset of Alzheimer's disease. The trial will monitor brain structure using positron emission tomography (PET) imaging, a method to see into the brain of living individuals. This trial will help determine if formoterol warrants further study as a possible way to improve brain function in people with Alzheimer's disease.